7-5987494-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000535.7(PMS2):c.1271T>C(p.Phe424Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000535.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461866Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727228
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Lynch syndrome Uncertain:2
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This missense variant replaces phenylalanine with serine at codon 424 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not specified Uncertain:1
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not provided Uncertain:1
This variant is denoted PMS2 c.1271T>C at the cDNA level, p.Phe424Ser (F424S) at the protein level, and results in the change of a Phenylalanine to a Serine (TTT>TCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Phe424Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Phenylalanine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Phe424Ser occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Phe424Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 424 of the PMS2 protein (p.Phe424Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 234733). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PMS2 function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.F424S variant (also known as c.1271T>C), located in coding exon 11 of the PMS2 gene, results from a T to C substitution at nucleotide position 1271. The phenylalanine at codon 424 is replaced by serine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Lynch syndrome 4 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at